Scope of medicinal flora as effective anti ulcer agents

Gastric ulcer generally results from persistent erosions and damage of the stomach wall which become perforated and develops into peritonitis and massive haemorrhage as a result of inhibition of the synthesis of mucus, bicarbonate and prostaglandins. The commercially available antiulcer drugs usually have various side effects. Due to these side effects, there is a need to find new antiulcerogenic compound(s) with potentially less or no side effects and medicinal plants have always been the main source of new drugs for the treatment of gastric ulcer. Several hundred plant genera are used medicinally mainly in the form of herbal preparation in indigenous system of medicine in different countries for the treatment of ulcers. In this review, we have given a detailed description of ulcer and its causative factors along with medicinal plants with antiulcer potency.


INTRODUCTION
The human stomach contains enumerable muscles that carry out the process of digestion and switch the different forms of food into digestive fluids which are pepsin and hydrochloric acid.These fluids make the food digest in the stomach.In order to attain this several organs integrate with each other which includes the central nervous system (CNS) and hormonal systems.The ulcer in the stomach may be the result of the disparity in the digestive fluids (Hoogerwerf, 2001).The over production of pepsin or hydrochloric acid may harm the line up of the stomach and cause ulcers in the stomach.Every year 4 million people are diagnosed with this disease.An estimated 6000 people die every year because of the complications associated with stomach ulcer.40, 000 people undergo surgery in order to get relief from the persistent symptoms of ulcer annually.An estimated 15,000 deaths occur as consequence of PUD.Indian pharmaceutical industry antacid and anti ulcer drugs share 6.2 billion rupees and occupy 4.3% in the market share (Jaikumar, 2010).Two main approaches for treating peptic ulcer include: reducing the production of gastric fluid and re-enforcing gastric mucosal protection (Valle, 2005).
Ulcers are defined as a breach in the mucosa of the alimentary tract, which extends through the muscularis mucosa into the submucosa or deeper (mayoclinic.com, 2011).Ulcus pepticum or PUD or peptic ulcer disease, is a chronic and most often solitary lesion that can be defined as mucosal erosions which is equal to or greater than 0.5 cm of an area of the gastrointestinal tract (mainly stomach and duodenum) which is usually acidic and extremely painful (Vakil, 2010;Chan, 2010).

Signs and symptoms
Abdominal pain, naturally epigastric with severity relating to mealtimes is usually after 1 h of taking a meal.Duodenal ulcers are classically relieved by food, while gastric ulcers are exacerbated by it; bloating and abdominal fullness; water brash (rush of saliva after an episode of regurgitation to dilute the acid in oesophagus); nausea, copious vomiting; loss of apetite and weight loss; hematemesis (vomiting of blood); melena (tarry, foulsmelling feces due to oxidized iron from hemoglobin); heart burn, gastroesophageal reflux disease (GERD) and use of certain forms of medication can raise the suspicion of peptic ulcer; and sudden increase in the abdominal pain or sharpness in the quality of the pain; vomiting blood or material that looks like coffee grounds; blood in stool or black, tarry stools (pharmacology2000.com, 2011) .
A gastric ulcer will give epigastric pain during the meal as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux into the stomach.Symptoms of duodenal ulcers will manifest mostly before the meal-when acid production stimulated by hunger is passed into the duodenum.This is not considered as reliable sign in clinical practice (Berroteran, 2002;Medina, 2010).

Helicobacter pylori
Helicobacter pylori was discovered in 1982 by two Australian Scientists, J. Robin Warren and Barry J. Marshall as a causative factor of ulcers.They showed that most stomach ulcers and gastritis were caused by colonization with this bacterium and not by stress or spicy food as had been assumed before.H. pylori is a spiral shaped Gram negative bacterium that lives in the acidic environment of the stomach.It is found in stomach along with acid secretion and can damage the tissue of the stomach and duodenum, causing inflammation and ulcers (Tiwari, 2005).H. pylori is believed to be transmitted from person to person through the oral cavity.The hypothesis that the mouth is a reservoir for H. pylori and a potential source of gastric infection is strengthened by several reports of H. pylori DNA in the saliva and dental plaque (Ahmed, 2006;Li, 1995;Olivier, 2006).
Other cause of ulcers is notably the gastric cancer.This especially occurs in ulcers of the greater curvature of the stomach in which most of them are a consequence of chronic H. pylori infection (Gloria, 2011;Saluja, 2002;Satoskar, 2007).It has been reported that H. pylori infection is a common problem in diabetic patients who have inadequate metabolic control where these micro organisms colonize the gastric antrum (Bikha, 2010).As diabetes and H. pylori are considered as major causes for dyspepsia, the incidence of H. pylori infection is higher in diabetic patients than in normal individuals (Roger and Sandhya et al. 505 Walker,2005).

Acid and pepsin
Powerful digestive fluids are alleged to contribute to the formation of ulcers.The stomach can protect itself from these fluids in several ways.These are produced as lubricant like mucus that coats the stomach and shields stomach tissues.They produce bicarbonate that neutralizes digestive fluids and breaks them down into less harmful substances.

NSAIDs
The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins.NSAIDs block the function of cyclooxygenase1, which is essential for the production of prostaglandins.NSAIDs can make the stomach vulnerable to the harmful effects of acid and pepsin by interfering with the stomach's ability to produce mucus and bicarbonate.

Smoking
Tobacco smoking leads to atherosclerosis and vascular spasms, causing vascular insufficiency and promoting the development of ulcers through ischemia.Nicotine contained in cigarettes can increase parasympathetic nerve activity to the GIT by acting on the nicotinic receptors at synapses-increase stimulation to the enterochromaffin like cells and G cells increases the amount of histamine and gastrin secreted, and therefore increases acidity of gastric juice (Tiwari, 2005).

Caffeine
Beverages and foods that contain caffeine can stimulate acid secretion in the stomach.This aggravates an existing ulcer, but the stimulation of stomach acid cannot be attributed solely to caffeine.

Alcohol
Heavy consumption of alcohol causes liver cirrhosis.Ulcers are found in people with liver cirrhosis.

Stress
Emotional stress do not cause ulcers, but people who are experiencing this often report increased pain in existing ulcers.Physical stress cause increase in risk of developing ulcers, especially in stomach.Examples of physical stress that can lead to ulcers are that suffered by people with injuries such as severe burns and people undergoing major surgery (Berroteran, 2002;Medina, 2010;Friedman,1998).

MECHANISM INVOLVED IN ULCERATION
Peptic ulcers are produced by an imbalance between the gastro duodenal mucosal defense mechanisms and damaging forces.Gastric acid and pepsin are requisite for all peptic ulcerations.Hyperacidity is not a prerequisite because only a minority of patients with duodenal ulcers has hyperacidity and is even less common in those with gastric ulcers (dyspepsy.com, 2011).Many bacteria have been found in the mucus, which was continuously secreted by mucus cells and removed on the luminal side.H. pylori is a bacterium, has flagella and moves through the stomach lumen and drills into the mucoid lining of the stomach.To avoid entry into the lumen, H. pylori senses the pH gradient within the mucus layer by chemotaxis and swims away from the acidic contents of the lumen towards the more neutral pH environment of the epithelial cell surface.H. pylori is also found on the inner surface of the stomach epithelial cells and occasionally inside epithelial cells.It produces cytotoxin associated gene A proteins (cag A) and vacuolating cytotoxins such as vacA, which activate the inflammatory cascade.H. pylori expresses sialic acid specific hemagluttinins and a lipid binding adhesins that mediate the binding to the mucosal surface.Gastrin is the main hormone involved in stimulating gastric acid secretion, and gastrin homeostasis is altered in H. pylori infection.The hyper acidity in duodenal ulcer may result from H. pylori induced hypergastrinemia.The elevation of gastrin may be a consequence of bacterial mediated decrease of antral D cells that secrete somastatin, thus using the inhibitory modulation of somatostatin on gastrin, or direct stimulation of gastrin cells by certain cytokines liberated during the inflammatory process.The organisms also elaborate phospholipases which damage surface epithelial cells and may release bioactive leukotrienes andeicosanoids.H. pylori produce large amounts of enzyme urease, molecules of which are localized inside and outside of the bacterium.Urease breakdown urea (which is normally secreted into the stomach) to carbondioxide and ammonia (ammonia is converted into the ammonium ion by taking hydrogen from water upon its breakdown into hydrogen and hydroxyl ions.Hydroxyl ions then react with carbondioxide, producing bicarbonate which neutralizes gastric acid.The survival of H. pylori in the acidic stomach is dependent on urease, and it would eventually die without the enzyme.The ammonia that is produced is toxic to the epithelial cells.Neutrophils attracted by H. pylori release myeloperoxidase which produces hypochlorous acid yield, in turn, monochloramine can destroy mammalian cells.In addition to H. pylori elaboration of enzymes, other antigens recruit inflammatory cells to the mucosa.The chronically inflamed mucosa is more susceptible to the acid injury.Finally, damaged mucosa is thought to permit leakage of tissue nutrients into the surface microenvironment thereby sustaining the bacillus.Mechanisms by which H. pylori could promote cancer are under investigation.One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cells mutation.The mechanism has been called "perigenetic pathway" and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins such as adhesion proteins.It has been proposed that H. pylori induces inflammation and locally high levels of TNF-α and/or interleukin 6.According to the proposed perigenetic mechanism, inflammation associated signaling molecules such as TNF-α can alter gastric epithelial cells adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes such as genes that code for cell adhesion proteins.

Gastrointestinal bleeding
Abrupt large bleeding which is life threatening can occur when the ulcer erodes one of the blood vessels.

Penetration
Herem the ulcer continues into the adjacent organs such as liver and pancreas.

Scarring and swelling
Scarring and swelling due to ulcers causes narrowing in the duodenum and gastric outlet obstruction, which causes severe vomiting.

Zollinger-Ellison syndrome
It is a rare syndrome which consists of a triad of non-beta islet cell tumors of the pancreas that contain and release gastrin, gastric acid hyper secretion and severe ulcer disease.Extra pancreatic gastrinomas are also common and may be found in the duodenal wall (Robbins and Cotran, 2006).

Diagnosis
An esophago gastro duodenoscopy (EGD) is a form of endoscopy, also known as gastroscopy, is carried out on patients in whom a peptic ulcer is suspected (Humphrey et al., 2008).The diagnosis of H. pylori can be made by: Urea breath test (non invasive and does not require EGD), direct culture from an EGD biopsy specimen, direct detection of urease activity in a biopsy specimen by rapid urease test, stool antigen test, histological examination and staining of an EGD biopsy.
If a peptic ulcer perforates, air will leak from inside the gastrointestinal tract which always contains some air into the peritoneal cavity which never contain air.This in turn lead to "free gas" within the peritoneal cavity.If the patient stands erect, while taking a chest X-ray, the gas will float to a point beneath the diaphragm.Thus in the peritoneal cavity, an erect chest X-ray or supine lateral abdominal X-ray will be obtained which is an open or perforated peptic ulcer disease.

Side effects of anti secretory agents
Rashes, diarrhoea, muscle pain, fatigue, bradycardia, blockade of cerebral H 2 receptors can cause drowsiness, mental confusion, delirium, hallucination.On long term use, it causes hepatotoxicity, gynecomastia, hyper prolactinemia.

Mechanism of proton pump inhibitors (PPI's)
PPI's decrease basal and stimulated gastric acid secretion during inhibition of acid secretion by parietal Sandhya et al. 507 cells, the H + /K + ATPase proton pump.These agents are most effective anti secretory agents.All medications in this class are week bases that must be activated by acid to inhibit the proton pump.Paradoxically, these prodrugs are acid labile compounds that can be degraded by stomach acid during oral administration and therefore available as enteric coated delayed release formulations.Once the drug reaches the higher pH of the duodenum, the enteric coating dissolves and the unprotanated prodrug readily penetrates the cell membranes, specifically that of parietal cells.As it traverses the parietal cell, and is exposed to intracellular acid, the prodrug becomes protonated and is no longer able to freely cross the cell membranes, thus the activated PPI becomes trapped in the parietal cell.Once formed, the active sulphonamide moiety covalently binds to H + /K + ATPase and inhibits acid secretion.Food may delay the absorption of some agents, but because PPI's require accumulation and acid activation, and because they inhibit only proton pumps that are actively secreting acid, they are most effective when taken on an empty stomach, shortly before meals (Satoskar, 2007).

TREATMENT OF H. PYLORI INFECTION
Once H. pylori is detected in patients with peptic ulcer, it has to be eradicated and the ulcer is allowed to heal.The standard first line therapy is a one week triple therapy consisting of proton pump inhibitor such as omeprazole and antibiotics like clarithromycin amoxycillin.
An increasing number of infected individuals are found to wharf antibiotic-resistant bacteria.This results in initial treatment failure and requires additional rounds of antibiotic therapy or alternative strategies such as a quadruple therapy (Table 1), which adds a bismuth colloid.For the treatment of clarithromycin-resistant strains of H. pylori use of levofloxacin as part of therapy is optional (Tiwari, 2005).

Prevention
plenty of vegetables rich in beta carotene, fruit containing vitamin C, zinc rich foods such as whole grains and sea food (oysters) should be eaten.Eating more vegetables and fruit such as carrots, kale, red and green peppers, citrus fruits, apricots, kiwi fruit may promote healing of peptic ulcers and protect against further damage to the gut wall.The helpful nutrients in these foods are βcarotene, which the body converts to vitamin A and C. Foods rich in zinc such as whole grains and seafood, can also help in the healing process.Essential fatty acids (found in fish oils and seed oils) may help to protect against ulcers by increasing the production of prostaglandlins (a group of compounds, one function of which is protect the lining of the alimentary canal).Table 2. List of few medicinal plants scientifically proven for anti ulcer activity (Dharmani, 2006;Sandhya, 2010).Intake of salt, soya sauce, spicy foods, caffeine in coffee, tea, cola drinks and alcohol should be cut down on.Large meals should be avoided, as they can encourage the production of excessive acid.Sufferers may also find that chilli peppers, black pepper, mustard and other strong spices such as those found in curries may aggravate their symptoms (Reader's Digest, 1996).

Medicinal plants as potent anti ulcer agents
Medicinal plants form the backbone of traditional systems of medicine in India.Phytochemicals from medicinal plants serve as lead compounds in drug discovery and design.Medicinal plants are rich source of novel drugs that forms the ingredients in traditional systems of medicine, modern medicines, nutraceuticals, food supplements, folk medicines, pharmaceutical intermediates, bioactive principles and lead compounds in synthetic drugs.WHO pointed out that more than 80% of world's population depends on plants to meet their primary health care need.India is one of the 12 mega diversity countries in the world so it has a vital stake in conservation and sustainable utilization of its biodiversity resources.Plant extracts are some of the most attractive sources of new drugs and have been shown to produce promising results for the treatment of gastric ulcer.Nearly 240 medicinal plants and 21 plants based compounds were identified as anti ulcer agents so far (shodhganga.inflibnet.ac.in, 2011) (Table 2 and 3).

Conclusion
Medical treatments are effectual for some people, but not for everyone.They cause many superfluous side effects and make symptoms worse.As doctors continue to prescribe the same antibiotics, H. pylori resistance will continue to increase and the medications will become less effective.For minimizing the side effects, potent herbal drugs which can eradicate all traces of H. pylori is the better choice.

Table 1 .
Triple and quadruple regimen for treatment of H. pylori induced ulcers.